Vascular smooth muscle cells (SMCs) are highly specialized cells that express high levels of SMC-specific proteins, such as smooth muscle myosin heavy chain (SMMHC/Myh11) and smooth muscle-?ctin (?A/Acta2)1. Under pathological conditions, however, SMCs are capable of undergoing profound phenotypic and functional changes resulting in a proliferative, inflammatory phenotype. An important paradigm shift in recent years suggests that vascular progenitor cells (VPCs) reside in a specialized niche within the adventitia of postnatal vessels. Adventitial VPCs express several stem cell markers, including Sca1 and CD34, have the capacity to differentiate in vitro into multiple lineages in response to specific signals, and potentially contribute to intimal lesions in vivo. However, important unanswered questions remain, including their origin, their degree of pluripotency and/or heterogeneity, and their contribution to vessel maintenance, repair, and pathological lesion formation. Using an innovative in vivo fate-mapping approach to genetically label mature Myh11- expressing SMC, we definitively established that mature SMCs give rise to the majority of intimal SMCs in response to wire-induced injury. Quite unexpectedly, we made the observation that some mature SMCs reverse migrate into the adventitia, exhibit no detectable expression of SM markers, but gain expression of Sca1 and CD34. We established that a distinct subpopulation of AdvSca1 progenitors arise from mature SMCs through a process we are calling endogenous adventitial reprogramming and suggest these cells play important roles in arterial homeostasis and disease. Our preliminary findings suggest SMC-derived AdvSca1 cells reside in the adventitia and contribute to a heterogeneic population of resident VPCs that possess distinct biological properties and fate decisions. Our overall hypothesis is that mature SMCs are reprogrammed during the later stages of vascular development to a subpopulation of functionally distinct VPCs; reprogramming is dependent at least in part on induction of the transcription factor, Klf4 and loss of the tumor suppressor, PTEN. After vascular injury, mobilization and recruitment of these cells contributes to intimal lesion formation and vessel repair. Our data could have a profound impact on defining the endogenous molecular mechanisms underlying the formation and maintenance of resident VPCs, which could lead to the potential to manipulate these cells in situ to improve therapeutic applications in settings suc as atherosclerosis/restenosis, aneurysm formation, ischemic tissues, and tumor angiogenesis. Mature macrovessel SMCs, as the source of resident VPCs, involving more than SMC dedifferentiation, but reprogramming to a functional progenitor phenotype, has not been described. Three Aims are proposed to define the differentiation potential and response of SMC- derived VPCs to vascular injury (Aim One), to define the role of Klf4 and PTEN on SMC reprogramming and identify essential endogenous pathways involved in SMC reprogramming (Aim Two), and define the in vivo fate and function of SMC-derived VPCs in response to vascular injury (Aim Three).